Severe and refractory anaphylaxis in pediatric intensive care unit
Authors: Guillaume Pouessel, Capucine Trochu, Flore Chagnon, Rémy Diesnis, Stéphane Leteurtre, Antoine Deschildre
Journal: Allergy (2023)

Data regarding severe anaphylaxis (SA) are limited. A new entity called refractory anaphylaxis (RA) has emerged in the literature, although there are subtle differences between the three definitions proposed (Table S1).1-3 A 21-member panel of experts in United States (US) has proposed RA to be defined as reactions treated with ≥3 appropriate doses of adrenaline (or initiation of an intravenous [IV] adrenaline infusion) in addition to symptom directed medical management (Table S1).3 RA appears to be rare, around 2% of anaphylaxis.4 We previously reported a cohort of 166 children (<18 years) admitted to pediatric intensive care units (PICU) for anaphylaxis (2003–2013).5 In the current study, we identified which of these children met the US definition for RA, and how they compared with those who were treated with ≥2 adrenaline doses and additional therapy which we defined as SA, and determined risk factors for either SA or RA (Methods in Appendix S1). Data were missing for 32 children, and so the analysis cohort consisted in children, of whom 70 (51%) had SA and 52 (38%) had RA (Table 1). Drugs were the most common elicitor for both SA and RA, followed by foods. SA and RA occurred mainly in hospital (67% and 71%, respectively) and in operating theatre (36% and 40%), or during an oral food challenge (OFC) (13% and 12%). The treatment and clinical symptoms according to organ system involvement from the first medical rescue to the first 24 h in PICU are described by time periods in children with either SA or RA (Figure 1 and Figure S1). Rapid clinical recovery has been reported with a normal examination within the first 6 h from PICU admission in the majority of children. However, three fatal anaphylaxis have been recorded, all related to foods and one following an OFC. Children with RA were less likely to have a history of asthma (p = .04) or prior anaphylaxis (p = .05), although these were not significant at multivariate logistic analysis, possibly because these are less common in children with drug-induced anaphylaxis. RA-cases were more likely to receive IV bolus adrenaline (p < .001), IV adrenaline infusion (p < .001), and mechanical ventilation (p = .015) during the first 24 h in PICU (Table S2). With regards to adrenaline route according to elicitors and places of reaction, a majority of children treated with IV adrenaline had a drug-related anaphylaxis (58%) mostly in a perioperative setting (76%) (Tables S3 and S4). IM adrenaline was mostly used for food-related anaphylaxis (39%) and rarely in a perioperative setting (7%). In a multivariate logistic analysis, hypotonia at first medical rescue was the only factor predicting both SA (OR: 4.05; 95% CI: 1.24–13.28; p = .02) and RA (OR: 5.73; 95% CI: 1.62–20.26; p = .01) (Table S5). Our data are the first to describe in details a series of children admitted to PICU for SA and even RA regarding their main characteristics, the time course of clinical manifestations and treatment. Whereas food is the main elicitor of anaphylaxis in children, drug was here the most common elicitor of both SA and RA, mainly in a perioperative setting, which is also reported by the European Anaphylaxis Registry.2 However, foods are common in SA. SA occurred during an OFC in 9/51 (18%) food-related anaphylaxis cases and RA in 6/51 (12%), which reinforce the need to follow a rigorous procedure for OFC implementation with a team trained to manage SA. In RA, the use of IV adrenaline infusion and fluid therapy was insufficient in contradiction with current guidelines.1 Our data highlight how difficult it is to identify the patients the most at risk of SA or even RA, as previously reported.6 However, we found that hypotonia at first medical rescue was a critical characteristic independently associated with either SA or RA. A worldwide consensus on RA definition is now urgently required as well as registries from childhood to elderly to better characterize risk factors and specificities according to age or elicitors. We acknowledge the members of the French Group for Paediatric Intensive Care and Emergencies for their contribution to this survey. GP has provided consultation and speaker services for Aimmune Therapeutics/Nestlé, Bausch and Lomb, Stallergenes, Novartis, ALK-Abello, Bioprojet; serves as a medical consultant/advisor for Bioprojet and AI Therapeutics/Nestlé. AD reports personal fees from Novartis, ALK, GSK, Sanofi, Regeneron, Aimmune Therapeutics, DBV Technologies, Nestlé, Stallergenes Greer, DBV Technologies, Nutricia. Grant from Fondation du Souffle, Conseil Régional Hauts-de-France Research Program 2014–2018, outside the submitted work. The other authors declare to have no conflict of interest. The other co-authors declare no conflict of interest in relation with this work. Pierre Tourneux (MD, PhD, Amiens), Gerald Boussicault (MD, Angers), Gérard Thiriez (MD, PhD, Besançon), Olivier Brissaud (MD, PhD, Bordeaux), Armelle Garenne (MD, Brest), Mickael Jokic (MD, Caen), Isabelle Petit (MD, Clermont-Ferrand), Denis Semama (MD, Dijon), Jean Bergounioux (MD, PhD, Garches), Thierry Debillon (MD, PhD, Grenoble), Isabelle Wroblewski (MD, Grenoble), Aimée Dorkenoo (MD, Lille), Eric Mallet (MD, Limoges), Etienne Javouhey (MD, PhD, Lyon), Blandine Vanel (MD, Lyon), Renaud Vialet (MD, Marseille- Hopital Nord), Fabrice Michel (MD, PhD, Marseille -Hôpital Timone), Gilles Cambonie (MD, PhD, Montpellier), Christophe Milesi (MD, Montpellier), Noël Boussard (MD, Nancy), Nicolas Joram (MD, Nantes), Didier Dupont (MD, PhD, Nice), Pierre Tissières (MD, PhD, Paris-Bicêtre), Stéphane Dauger (MD, PhD, Paris-Robert Debré), Sylvain Renolleau (MD, PhD, Paris-Necker), Pierre-Louis Léger (MD, PhD, Paris-Trousseau), Thierry Mansir (MD, Pau), Jean-Pascal Saulnier (MD, Poitiers), Nathalie Bednarek (MD, PhD, Reims), Olivier Tirel (MD, Rennes), Thierry Blanc (MD, Rouen), Hugues Patural (MD, PhD, Saint-Etienne), Dominique Astruc (MD, Strasbourg), Marie-Odile Marcoux (MD, Toulouse), Romain Amadieu (MD, Toulouse), Julie Chantreuil (MD, Tours). Appendix S1. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.